Innate dysfunction promotes linear growth failure in pediatric Crohn's disease and growth hormone resistance in murine ileitis.

Abstract

BACKGROUND:

Growth failure remains a common complication of pediatric Crohn's disease (CD) and has been associated with small bowel involvement and need for surgery. We have reported that patients with elevated (≥ 1.6 μg/mL) granulocyte macrophage colony stimulating factor autoantibodies (GM-CSF Ab) are more likely to experience complicated ileal disease requiring surgery. We hypothesized that concurrent GM-CSF Ab and CARD15 risk allele carriage (C15(+) GMAb(+) ) would be associated with growth failure in CD and growth hormone (GH) resistance in murine ileitis.

METHODS:

We enrolled 229 pediatric CD patients at two sites and determined CARD15 genotype, serum GM-CSF Ab, and GH binding protein (GHBP), and height (HTz) and weight (WTz) z-scores at diagnosis. Ileitis was induced in card15-deficient mice by GM-CSF neutralization and nonsteroidal antiinflammatory drug (NSAID) exposure. Hepatic GH receptor (GHR) abundance and GH-dependent Stat5 activation were determined by western blot and Igf-I mRNA expression by real-time polymerase chain reaction (PCR).

RESULTS:

Mean (95% confidence interval [CI]) HTz at diagnosis was reduced to -0.48 (-4.2, 2.3) in C15(+) GMAb(+) patients, compared to -0.07 (-4.9, 3.4) in disease controls (P ≤ 0.05). Circulating GHBP, as a marker for tissue GHR abundance, was reduced in C15(+) GMAb(+) patients. Hepatic GHR abundance, GH induction of Stat5 tyrosine phosphorylation, and Igf-I mRNA expression were reduced in male card15-deficient mice with ileitis due to GM-CSF neutralization and NSAID exposure.

CONCLUSIONS:

Innate dysfunction due to concurrent genetic variation in CARD15 and neutralizing GM-CSF Ab is associated with linear growth failure in pediatric CD, and hepatic GH resistance in murine ileitis.

• Authors: Sharon D'Mello, Anna Trauernicht, Anne Ryan, Erin Bonkowski, Tara Willson, Bruce C Trapnell, Stuart J Frank, Subra Kugasathan, Lee A Denson
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 18 Issue 2 Pg. 236-45 (Feb 2012) ISSN: 1536-4844 [Electronic] England
• PMID: 21337672 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 Crohn's & Crohn's & Colitis Foundation of America, Inc.

Chemical References

• Autoantibodies
• Carrier Proteins
• NOD2 protein, human
• Nod2 Signaling Adaptor Protein
• Nod2 protein, mouse
• Receptors, Somatotropin
• STAT5 Transcription Factor
• Granulocyte-Macrophage Colony-Stimulating Factor
• Growth Hormone
• somatotropin-binding protein

Topics

• Adolescent
• Animals
• Autoantibodies (blood)
• Body Height
• Body Weight
• Carrier Proteins (blood)
• Child
• Child, Preschool
• Crohn Disease (physiopathology)
• Failure to Thrive (physiopathology)
• Female
• Granulocyte-Macrophage Colony-Stimulating Factor (immunology)
• Growth Hormone (physiology)
• Humans
• Ileitis (chemically induced, physiopathology)
• Infant
• Liver (chemistry)
• Male
• Mice
• Mice, Knockout
• Nod2 Signaling Adaptor Protein (genetics)
• Receptors, Somatotropin (analysis)
• Retrospective Studies
• STAT5 Transcription Factor (physiology)